Summary: Persistent infection of adult mink with Aleutian mink disease parvovirus (ADV) leads to disturbances of immune regulation, probably mediated by restricted, non-cytopathic replication of ADV in macrophages. In contrast, infection of mink kits is acute, and ADV replication is permissive and cytopathic. Permissive replication requires the activity of caspases, cysteine proteases activated during apoptosis, to cleave the virus? major nonstructural protein NS1. We have recently demonstrated that this cleavage of NS1 generates a C-terminal product that binds to full-length NS1 and facilitates its nuclear localization. In addition, the C-terminal product can be supplied in trans and rescue the replication of a mutant ADV virus encoding an uncleavable NS1. We have also identified the nuclear localization sequence in the C-terminal product responsible for directing the nuclear transport of the NS1 oligomer. Since nuclear localization of NS1 is required for its functions in virus replication, these findings explain the mechanism whereby caspase activation mediates virus replication. If caspases are not activated following ADV infection, which may occur during infection of macrophages, virus replication would be restricted. Caspase-dependent replication may be an important mechanism utilized by normally lytic viruses that initiate restricted, persistent infections in vivo. A second aim of the laboratory is to examine the use of specific cell receptors by ADV and a second parvovirus of mink, mink enteritis virus (MEV). ADV and MEV both infect Crandell feline kidney (CrFK) cells, and MEV is assumed to use the transferrin receptor to enter susceptible cells. Using RNA silencing technology, we have shown that MEV requires the transferrin receptor to infect CrFK cells, while ADV can infect transferrin-negative cells and therefore does not require this receptor for virus entry. In addition, MEV does not require caspases for permissive replication. These fundamental differences in the biology of the two viruses may contribute to the different pathogenesis exhibited in infected adult mink.